Brain-Derived Neurotrophic Factor Expression in Asthma. Association with Severity and Type 2 Inflammatory Processes

Abstract

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, exists in several isoforms, which differentially impacts neuronal and immune cell survival and differentiation. The role of BDNF and its isoforms in asthma remains unclear. The objectives of this study were to compare the BDNF protein isoforms and specific splice variant expression in sputum and bronchoscopic samples from healthy control subjects and participants with asthma, and to relate these changes to findings in IL-13-stimulated human airway epithelial cells. Sputum and bronchoscopic samples from healthy control subjects and participants with asthma were evaluated for BDNF protein (ELISA and Western blot) and BDNF mRNA (gel and quantitative real-time PCR) in relation to asthma severity and type 2 inflammatory processes. BDNF mRNA was measured in cultured primary human airway epithelial cells after IL-13 stimulation. Total BDNF protein differed among the groups, and its mature isoform was significantly higher in sputum from subjects with severe asthma compared with healthy control subjects (overall P = 0.008, P = 0.027, respectively). Total BDNF was higher in those with elevated fractional exhaled nitric oxide and sputum eosinophilia. In vitro, IL-13 increased BDNF exon VIb splice variant and the ratio to BDNF common exon IX mRNA (P < 0.001, P = 0.003, respectively). Epithelial brushing exon VIb mRNA and total BDNF protein differed among the groups and were higher in subjects with severe asthma than in healthy control subjects (overall P = 0.01, P = 0.02, respectively). The mature BDNF isoform and the exon VIb splice variant are increased in human asthmatic airways. The in vitro increase in response to IL-13 suggests that type 2 cytokines regulate BDNF levels and activity in asthma.

Mechanisms of BDNF regulation in asthmatic airway smooth muscle

“…We previously showed that BDNF acts like a growth factor, working in conjunction with inflammatory mediators relevant to asthma, such as TNF-␣ and IL-13, to modulate [Ca 2ϩ ] i (37) and ASM proliferation (7). In the airway, BDNF can be secreted by a variety of cell types, including immune cells, neurons, epithelial cells, and smooth muscle cells, and recently, BDNF expression and regulation, as well as its action via TrkB in these cells, have gained attention as a potentially significant mechanism in the pathogenesis of asthma (33,35,44,49). The data presented in the current study present a picture of complex regulation of endogenous BDNF expression and secretion by human ASM in the context of inflammation (represented by TNF-␣) and highlight a potential autocrine role for this neurotrophin.…”

“…Recently, enhanced BDNF expression in epithelium of severe asthmatics has garnered interest in the idea that local BDNF expression and effects may be important in asthma phenotypes (49). We have shown that ASM responds to exogenous BDNF with elevated intracellular Ca 2ϩ ([Ca 2ϩ ] i ) and cell proliferation, particularly in the presence of cytokines such as TNF-␣ and IL-13 (1,7,34,37).…”

“…We have shown that ASM responds to exogenous BDNF with elevated intracellular Ca 2ϩ ([Ca 2ϩ ] i ) and cell proliferation, particularly in the presence of cytokines such as TNF-␣ and IL-13 (1,7,34,37). However, ASM appears to be not only a target, but also a source of BDNF (1,7,44,45,49). What is less understood are the mechanisms by which local (airway) BDNF is regulated.…”

Secreted Brain-Derived Neurotrophic Factor and Asthma Severity

“…Regarding the cellular source, Wang and colleagues previously showed Ca 21 -dependent regulation of BDNF secretion in human airway smooth muscle (ASM) (1). In contrast, we focused on epithelial cells and did not address ASM expression.…”

“…All these reports obviously raise questions regarding cell sources versus targets of BDNF. Watanabe and colleagues demonstrate a potential relationship between altered BDNF isoforms in airway epithelial cells with asthma severity (1). Here, the contribution of the Th2 cytokine IL-13 in regulating BDNF exon VIb splice variant expression in sputum and in epithelial cells points to bronchial epithelium as at least one source.…”